On February 20, 2024 Bristol Myers Squibb (NYSE: BMY) reported that the U.S. Food and Drug Administration (FDA) has accepted for priority review the supplemental new drug application (sNDA) for KRAZATI (adagrasib) in combination with cetuximab for the treatment of patients with previously treated KRASG12C-mutated locally advanced or metastatic colorectal cancer (CRC) (Press release, Bristol-Myers Squibb, FEB 20, 2024, View Source [SID1234640258]). The FDA assigned a Prescription Drug User Fee Act (PDUFA) goal date of June 21, 2024.

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"Pretreated KRASG12C-mutated CRC is associated with poor outcomes and the current standard of care offers limited clinical benefit for patients," said Anne Kerber, senior vice president, head of late clinical development, Hematology, Oncology, Cell Therapy (HOCT) at Bristol Myers Squibb. "The acceptance of this filing for KRAZATI in combination with cetuximab is a positive step toward providing a potential new option for patients and their physicians. It reinforces our commitment to developing potentially transformative targeted cancer therapies for patients for whom few treatment options exist."

The submission is based on the results of KRYSTAL-1 study, a multicohort trial which evaluated KRAZATI alone or in combination with other anticancer therapies in patients with advanced solid tumors harboring a KRASG12C mutation. The primary endpoint for the registrational cohort was objective response rate. The secondary endpoints for the pooled cohorts included duration of response, progression-free survival, overall survival and safety.

Results of the KRYSTAL-1 study showed that KRAZATI was well tolerated and provided promising clinical activity in pretreated patients with locally advanced or metastatic CRC harboring a KRASG12C mutation. The safety profile for KRAZATI plus cetuximab was manageable and consistent with previous reports, and with the known safety profile of each drug individually.

ABOUT KRAZATI (adagrasib)

KRAZATI (adagrasib) is highly selective and potent oral small-molecule inhibitor of KRASG12C that is optimized to sustain target inhibition, an attribute that could be important to treat KRASG12C-mutated cancers, as the KRASG12C protein regenerates every 24-48 hours. KRASG12C mutations act as oncogenic drivers and occur in approximately 14% of NSCLC (adenocarcinoma), 3-4% of colorectal cancer, and 1-2% of several other cancers.

In 2022, KRAZATI was granted accelerated approval for treatment of adult patients with KRASG12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), as determined by an FDA-approved test, who have received at least one prior systemic therapy. This indication is approved under accelerated approval based on objective response rate (ORR) and duration of response (DOR). Continued approval for this indication may be contingent upon verification and description of a clinical benefit in a confirmatory trial(s).

In 2024, the European Commission (EC) granted conditional marketing authorization for KRAZATI as a targeted treatment option for adult patients with KRASG12C-mutated advanced NSCLC and disease progression after at least one prior systemic therapy.

KRAZATIcontinues to be evaluated as monotherapy and in combination with other anti-cancer therapies in patients with advanced KRASG12C-mutated solid tumors, including NSCLC and colorectal cancer.

In 2022, the FDA granted breakthrough therapy designation for KRAZATI in combination with cetuximab in patients with KRASG12C-mutated advanced colorectal cancer (CRC) whose cancer has progressed following prior treatment with chemotherapy and an anti-VEGF therapy.

For Prescribing Information, visit KRAZATI.

ABOUT KRYSTAL-1

KRYSTAL-1 is an open-label, multicenter, multiple expansion cohort Phase 1/2 trial to determine the safety and efficacy of KRAZATI in patients with advanced solid tumors that harbor a KRASG12C mutation. The primary endpoint for the Phase 2 cohort of the KRYSTAL-1 study was objective response rate. Secondary endpoints included duration of response, progression-free survival, overall survival and safety.

INDICATION

KRAZATI is indicated for the treatment of adult patients with KRASG12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), as determined by an FDA-approved test, who have received at least one prior systemic therapy.

This indication is approved under accelerated approval based on objective response rate (ORR) and duration of response (DOR). Continued approval for this indication may be contingent upon verification and description of a clinical benefit in a confirmatory trial(s).

IMPORTANT SAFETY INFORMATION

GASTROINTESTINAL ADVERSE REACTIONS

In the pooled safety population, serious gastrointestinal adverse reactions observed were gastrointestinal obstruction in 1.6%, including 1.4% grade 3 or 4, gastrointestinal bleeding in 0.5% of patients, including 0.5% grade 3, and colitis in 0.3%, including 0.3% grade 3. In addition, nausea, diarrhea, or vomiting occurred in 89% of 366 patients, including 9% grade 3. Nausea, diarrhea, or vomiting led to dosage interruption or dose reduction in 29% of patients and permanent discontinuation of KRAZATI in 0.3%
Monitor and manage patients using supportive care, including antidiarrheals, antiemetics, or fluid replacement, as indicated. Withhold, reduce the dose, or permanently discontinue KRAZATI based on severity
QTC INTERVAL PROLONGATION

KRAZATI can cause QTc interval prolongation, which can increase the risk for ventricular tachyarrhythmias (eg, torsades de pointes) or sudden death
In the pooled safety population, 6% of 366 patients with at least one post-baseline electrocardiogram (ECG) assessment had an average QTc ≥501 ms, and 11% of patients had an increase from baseline of QTc >60 msec. KRAZATI causes concentration-dependent increases in the QTc interval
Avoid concomitant use of KRAZATI with other products with a known potential to prolong the QTc interval. Avoid use of KRAZATI in patients with congenital long QT syndrome and in patients with concurrent QTc prolongation
Monitor ECGs and electrolytes prior to starting KRAZATI, during concomitant use, and as clinically indicated in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, and in patients who are taking medications that are known to prolong the QT interval. Withhold, reduce the dose, or permanently discontinue KRAZATI, depending on severity
HEPATOTOXICITY

KRAZATI can cause hepatotoxicity
In the pooled safety population, hepatotoxicity occurred in 37%, and 7% were grade 3 or 4. A total of 32% of patients who received KRAZATI had increased alanine aminotransferase (ALT)/increased aspartate
aminotransferase (AST); 5% were grade 3 and 0.5% were grade 4. Increased ALT/AST leading to dose interruption or reduction occurred in 11% of patients. KRAZATI was discontinued due to increased ALT/AST in 0.5% of patients
Monitor liver laboratory tests (AST, ALT, alkaline phosphatase, and total bilirubin) prior to the start of KRAZATI, and monthly for 3 months or as clinically indicated, with more frequent testing in patients who develop transaminase elevations. Reduce the dose, withhold, or permanently discontinue KRAZATI based on severity
INTERSTITIAL LUNG DISEASE /PNEUMONITIS

KRAZATI can cause interstitial lung disease (ILD)/pneumonitis, which can be fatal. In the pooled safety population, ILD/pneumonitis occurred in 4.1% of patients, 1.4% were grade 3 or 4, and 1 case was fatal. The median time to first onset for ILD/pneumonitis was 12 weeks (range: 5 to 31 weeks). KRAZATI was discontinued due to ILD/pneumonitis in 0.8% of patients
Monitor patients for new or worsening respiratory symptoms indicative of ILD/pneumonitis (eg, dyspnea, cough, fever). Withhold KRAZATI in patients with suspected ILD/pneumonitis and permanently discontinue KRAZATI if no other potential causes of ILD/pneumonitis are identified
ADVERSE REACTIONS

The most common adverse reactions (≥25%) are nausea, diarrhea, vomiting, fatigue, musculoskeletal pain, hepatotoxicity, renal impairment, edema, dyspnea, decreased appetite
FEMALES AND MALES OF REPRODUCTIVE POTENTIAL

Infertility: Based on findings from animal studies, KRAZATI may impair fertility in females and males of reproductive potential
Please see U.S. Full Prescribing Information for KRAZATI.

About Colorectal Cancer

Colorectal cancer (CRC) is cancer that develops in the colon or the rectum, which are part of the body’s digestive or gastrointestinal system. CRC is the third most commonly diagnosed cancer in the world. In 2020, it is estimated that there were approximately 1,931,000 new cases of the disease; it is the second leading cause of cancer-related deaths among men and women combined.